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Disassembly and rewiring of synaptic connectivity in the inner retina in experimental glaucoma

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Abstract Number: 6440

AuthorBlock: Yvonne Ou1, Alfred K. Yu1, Kelly Mai1, Alan Tran1, Luca Della Santina1
1Ophthalmology, University of California, San Francisco, San Francisco, California, United States;

DisclosureBlock: Yvonne Ou, None; Alfred K. Yu, None; Kelly Mai, None; Alan Tran, None; Luca Della Santina, None;

Purpose
Disruptions of synaptic connectivity between bipolar cells (BCs) and retinal ganglion cells (RGCs) are among the earliest pathologic events in the inner retina following transient ocular hypertension. It is not known whether the adult retina has the potential for rewiring or recovery of synaptic connectivity at the BC-RGC synapse. Here we investigated the connectivity between individual RGCs and presynaptic BCs after intraocular pressure (IOP) elevation, specifically for anatomic and functional evidence of rewiring and recovery.

Methods
Laser photocoagulation of the episcleral and limbal vessels was performed unilaterally in adult CD-1 mouse eyes, generating transient IOP elevation lasting 7 days. Whole-mount retinas were biolistically transfected to label RGCs and their excitatory postsynaptic sites (PSD95). Immunostaining with CtBP2 labeled presynaptic ribbons while immunostaining with Synaptotagmin-2 and PKCalpha labeled axon terminals of Type 6 and rod bipolar cells, respectively. RGC connectivity was measured by colocalization analysis in three dimensions using ObjectFinder on confocal Z-stacks of individual RGC dendrites at 7, 14, and 30 days after IOP elevation. Longitudinal scotopic flash ERG recordings were also performed at these same time points. Statistics were performed using the Wilcoxon-Mann-Whitney rank-sum test.

Results
We examined the alpha ON-sustained RGC because of its known synaptic circuitry both in development and adulthood. The main bipolar cell partner of the alpha ON-sustained RGC is the type 6 bipolar, and there is preferential loss of this major partner as early as 7 days after IOP elevation (64 vs. 37%, control vs. laser; p=0.001). Surprisingly, 30 days after IOP elevation, we found evidence of rewiring with a new partner, namely the rod bipolar cell (5.2% vs. 12.3% rod bipolar cell inputs, control vs. laser; p=0.0043). Furthermore, the normalized scotopic b wave initially showed a depressed amplitude but eventually recovered to control level amplitude by 30 days after IOP elevation.

Conclusions
The alpha ON-sustained RGC preferentially loses its major bipolar cell partner (type 6) early after transient IOP elevation. However, over time new bipolar cell partners, namely rod bipolar cells, rewire with these RGCs. Together with recovery of the scotopic b wave amplitude, these data suggest that the adult diseased retina may exhibit circuit-level plasticity.

Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details.
It is not known whether neurons in the mature retina can form new connections with new partners. We found that in glaucoma, a disease in which the retinal ganglion cell degenerates, that this cell can form new connections with new partners, raising the possibility that the diseased retina can recover after injury.